Challenges in the management of new daily persistent headache at a tertiary headache center-A retrospective real-world evidence study.

OBJECTIVE: In this retrospective cross-sectional real-world evidence study from the Danish Headache Center (DHC), a national tertiary headache center in Denmark, we sought to identify potential pharmacological agents for the treatment of new daily persistent headache (NDPH). BACKGROUND: NDPH is an enigmatic headache disorder with abrupt onset and chronic duration for which evidence-based treatments are lacking. NDPH is a diagnosis of exclusion, for which secondary headaches must be ruled out and the etiology remains idiopathic. The sparse investigations of this disorder have not yielded a pathophysiological basis and no effective treatment for NDPH has been found. METHODS: All patients with an NDPH diagnosis at the DHC were enrolled (n = 64). First, we reviewed the records of all patients with an NDPH diagnosis to evaluate whether they fulfilled the diagnostic criteria. Next, we extracted all the trialled acute and prophylactic pharmacological interventions for the included patients. Then, pharmacological interventions that had been tried in ≥ 20 patients were analyzed post hoc with efficacy as the outcome, which was stratified in five effect categories ("no effect," "partial effect," "full effect," "partial effect and cessation due to adverse events," and "full effect and cessation due to adverse events"). Descriptive statistical analysis was performed, and the results were schematically presented (see Table 2). RESULTS: Fifty-one patients out of 64 were found to fulfill NDPH criteria and were included in the study. The drugs tried by ≥ 20 patients were amitriptyline (n = 34), candesartan (n = 27), and mirtazapine (n = 20). No patients experienced a complete effect with these drugs while 9% (3/34), 26% (7/27), and 15% (3/20) experienced a partial effect with no adverse events that led to treatment discontinuation, respectively. The remaining patients experienced either no effect or a partial effect with adverse events leading to treatment discontinuation. CONCLUSION: In this study we add real-world evidence to suggest that prophylactic drugs conventionally used for treating chronic migraine and chronic tension-type headache have limited utility for treating NDPH; however, a partial response in 26% of patients using candesartan and 15% of patients using mirtazapine warrants further investigation in randomized double-blinded placebo-controlled trials.

Pericranial Muscle Stiffness, Pain Thresholds, and Tenderness during a Treatment Cycle of OnabotulinumtoxinA for Chronic Migraine Prevention.

BACKGROUND: Treatment with OnabotulinumtoxinA (BoNT-A) is effective as a preventive treatment for chronic migraine (CM). Preclinical studies suggest that the mechanism of action of BoNT-A in migraine is based on blocking unmyelinated C fibers. We aimed to investigate whether the muscle-relaxing effect of BoNT-A is associated with the preventive mechanism in patients with chronic migraine by measuring the stiffness, pain thresholds, and tenderness of the BoNT-A-applied muscles. METHODS: A total of 22 patients with CM who were already in BoNT-A treatment participated in this longitudinal prospective study. Pericranial muscle stiffness was measured using ultrasound shear wave elastography, which measures the speed of shear waves propagating through the muscle. Pressure pain thresholds (PPT) were obtained via algometry, and muscle tenderness was measured via manual palpation. Measurements were made before BoNT-A injections and six weeks after the treatment. The measurements were performed while the muscles were maximally relaxed. The patients also completed daily diaries on headache and neck pain. RESULTS: No change was observed in muscle stiffness (p = 0.737) or pericranial muscle tenderness (p = 0.400). The PPT over the trapezius muscles increased from 250 kPa before treatment to 304 kPa six weeks after treatment (p = 0.027). No change was observed on the temporalis muscles (p = 0.200) nor the non-dominant index finger (p = 0.067). BoNT-A decreased neck pain (p = 0.008) and headache (p = 0.007). CONCLUSIONS: The findings suggest that BoNT-A leads to the desensitization of cutaneous and muscle nociceptors in the head and neck regions, whereas muscle relaxation might not be an important part of the anti-migraine effect.

Serum calcitonin gene-related peptide in patients with persistent post-concussion symptoms, including headache: a cohort study.

BACKGROUND: Calcitonin gene-related peptide (CGRP) plays an important role in migraine pathophysiology, and post-traumatic headache (PTH) frequently presents with migraine-like features. Despite several clinical similarities, few studies have explored CGRP in PTH and concussion. This study investigates serum CGRP levels in patients with persistent post-concussion symptoms (PPCS), including PTH. METHODS: This cohort study was based on serum samples from individuals aged 18-30 years with PPCS who participated in a previously published randomized controlled trial of a non-pharmacological intervention. The primary outcome was serum CGRP concentrations, determined at baseline before randomization and at follow-up 7 months later, using an enzyme-linked immunosorbent assay (ELISA). CGRP levels at baseline were compared with healthy anonymous blood donors in the same age group. RESULTS: Baseline serum samples were collected from 86 participants with PPCS. The participants were most often female (78%) and migraine-like headache was the most frequent headache phenotype (74%). Serum CGRP levels were higher in participants with PPCS than in 120 healthy individuals (median: 158.5 pg/mL vs. 76.3 pg/mL, p = 0.050). A stratified analysis revealed that females with PPCS had a fivefold higher median than healthy females (166.3 pg/mL vs. 32.1 pg/mL, p = 0.0006), while no differences were observed in males (p = 0.83). At follow-up, CGRP levels decreased with a median change of - 1.3 pg/mL (95% confidence interval: - 17.6-0, p = 0.024). DISCUSSION: Elevated serum levels of CGRP in patients with PPCS and a decrease over time suggest an involvement of CGRP in PTH/PPCS. If confirmed in other studies, it could pave the way for CGRP-targeted therapies, which could have clinical significance.

Calcitonin gene-related peptide causes migraine aura.

BACKGROUND: Although the involvement of calcitonin gene-related peptide (CGRP) in migraines is well-established, its specific role in investigating the aura phase, which often precedes the headache, remains largely unexplored. This study aims to instigate CGRP's potential in triggering aura, thus establishing its role in the early stages of migraine. METHODS: In this open-label, non-randomized, single-arm trial, 34 participants with migraine with aura received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min on a single experimental day. Participants were required to be free of headache and report no use of acute medications 24 h before infusion start. The primary endpoint was the incidence of migraine aura during the 12-hour observational period after the start of infusion. RESULTS: Thirteen (38%) of 34 participants developed migraine aura after CGRP infusion. In addition, 24 (71%) of 34 participants developed migraine headache following CGRP infusion. CONCLUSIONS: Our findings suggest that CGRP could play an important role in the early phases of a migraine attack, including during the aura phase. These insights offer a new perspective on the pathogenesis of migraines with aura. They underscore the need for additional research to further explore the role of CGRP in these initial stages of a migraine attack, and potentially inform future development of therapeutic interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04592952.

Comparison of the blink reflex in classical and idiopathic trigeminal neuralgia.

BACKGROUND: Previous findings indicate that the blink reflex is useful to distinguish between primary (classical/idiopathic) and secondary trigeminal neuralgia. No prior studies have investigated whether the blink reflex could identify differences in electrophysiological responses between classical and idiopathic trigeminal neuralgia. With this in mind, we investigated the blink reflex in a cohort of classical and idiopathic trigeminal neuralgia patients. METHODS: Participants were consecutively enrolled in the study. According to magnetic resonance imaging findings, the patients were subgrouped into either classical or idiopathic trigeminal neuralgia. Assessors were blinded to the subgroup and pain side, and the blink reflex was examined to assess R1 and R2 latencies, as well as the area under the curve. RESULTS: The study group constituted of 55 patients with primary trigeminal neuralgia: 25 patients with classical trigeminal neuralgia and 30 patients with idiopathic trigeminal neuralgia. None of the blink reflex latencies (R1 and R2) or the area under the curve significantly differed between the two subgroups when adjusted for age and sex (p > 0.05). CONCLUSIONS: Our findings suggest that the blink reflex cannot be used to differentiate classical and idiopathic trigeminal neuralgia patients, and that both subgroups may share common pathophysiological mechanisms.Trial Registration: ClinicalTrials.gov Identifier: NCT05328661.

Adding eptinezumab to brief patient education to treat chronic migraine and medication-overuse headache: Protocol for RESOLUTION-A phase 4, multinational, randomized, double-blind, placebo-controlled study.

Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine. Methods and analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo (n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population. Ethics and dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results.

Fundus imaging and perimetry in patients with idiopathic intracranial hypertension-an intermethod and interrater validity study.

BACKGROUND AND PURPOSE: There is a need to improve the diagnostic process of patients suspected of papilledema. In patients with known or suspected idiopathic intracranial hypertension a fundus imaging and perimetric visual field assessment system (COMPASS) performed at a headache center was validated in comparison to an assessment (Topcon plus OCTOPUS) at a neuroophthalmological clinic. METHODS: For intermethod assessment, blinded fundus images and perimetry from COMPASS versus Topcon plus OCTOPUS were assessed by a neuroophthalmologist. For interrater assessment, fundus images and perimetry obtained by the COMPASS system were assessed by an untrained medical doctor, a trained neurologist and a trained medical student and compared to the neuroophthalmologist's assessments. RESULTS: For the intermethod variation of the presence of papilledema on fundus images, a kappa value of 0.60, sensitivity of 87% and specificity of 73% were found. The interrater variation of the presence of papilledema on fundus images showed kappa values ranging from 0.43 to 0.74, sensitivity values ranging from 70% to 96% and specificity values ranging from 46% to 93% when comparing the assessments made by the headache center staff with neuroophthalmologist's assessments. The COMPASS showed a 59% sensitivity and moderate agreement in detecting visual field defects compared with OCTOPUS. The visual field assessment showed only slight to fair agreement from 0.19 to 0.31 between assessments made by the headache center staff and the neuroophthalmologist. CONCLUSION: The COMPASS system can be used with reasonable sensitivity in the assessment of papilledema in patients suspected of idiopathic intracranial hypertension at a tertiary headache center.

Cortical hemodynamic response during cognitive Stroop test in acute stroke patients assessed by fNIRS.

BACKGROUND: Following acute ischemic stroke (AIS) many patients experience cognitive impairment which interferes neurorehabilitation. Understanding and monitoring pathophysiologic processes behind cognitive symptoms requires accessible methods during testing and training. Functional near-infrared spectroscopy (fNIRS) can assess activational hemodynamic responses in the prefrontal cortex (PFC) and feasibly be used as a biomarker to support stroke rehabilitation. OBJECTIVE: Exploring the feasibility of fNIRS as a biomarker during the Stroop Color and Word Test (SCWT) assessing executive function in AIS patients. METHODS: Observational study of 21 patients with mild to moderate AIS and 22 healthy age- and sex-matched controls (HC) examined with fNIRS of PFC during the SCWT. Hemodynamic responses were analyzed with general linear modeling. RESULTS: The SCWT was performed worse by AIS patients than HC. Neither patients nor HC showed PFC activation, but an inverse activational pattern primarily in superolateral and superomedial PFC significantly lower in AIS. Hemodynamic responses were incoherent to test difficulty and performance. No other group differences or lateralization were found. CONCLUSIONS: AIS patients had impaired executive function assessed by the SCWT, while both groups showed an inverse hemodynamic response significantly larger in HC. Investigations assessing the physiology behind inverse hemodynamic responses are warranted before deeming clinical implementation reasonable.

Telephone follow-up on treatment and patient satisfaction at a Danish tertiary headache center: A prospective study.

OBJECTIVE: We investigated whether telephone follow-up consultations could lead to appropriate adjustment of treatments and a higher degree of patient satisfaction among patients with migraine and tension-type headache (TTH). BACKGROUND: Migraine and TTH are disabling headache forms requiring optimized treatment. METHODS: In a prospective, non-randomized, quality control study with controls comparing telephone-interview intervention (TeII) with business-as-usual (BAU) treatment, we included newly referred patients with migraine and/or TTH. The TeII group was contacted by telephone by healthcare professionals at 8 and 16 weeks after the first visit addressing headache treatment. Electronic questionnaires were sent to all participants before the first visit and after 6 months. Predefined outcomes were number of patients with change in preventive and acute medication; change in headache frequency; migraine frequency; scores from the eight-item Headache Under-Response to Treatment (HURT-8) questionnaire, Insomnia Severity Index (ISI), and Hospital Anxiety and Depression Scale (HADS); and patient satisfaction after 6 months. RESULTS: From May 2020 to April 2021, there were 230 patients enrolled in the TeII program, whereof 96 patients were included in the analysis. For the BAU group, 91 patients with similar sex and age distribution were identified via medical-record reviews in the same period. More patients in the TeII group than in the BAU group had a change in acute medication (27/96 [28%] vs. five of 91 [6%], p < 0.001) and preventive medication (28/96 [29%] vs. 12/91 [13%], p = 0.006). Headache days per month decreased in the TeII group (-4.6, 95% confidence interval [CI] -6.5 to -2.7; p = 0.001) and the BAU group (-2.5, 95% CI -4.6 to -0.4; p = 0.018), without significant difference between the groups (p = 0.080). There was no difference in migraine frequency between the groups (TeII: 1.0 day, 95% CI, -1.3 to 1.0; BAU: 1.0 day, 95% CI, -2.5 to 0.5; p = 0.718) or HURT-8 score (TeII: 10.5, 95% CI 9.5-11.5; BAU: 13.0, 95% CI 11.7-14.2; p = 0.053). There were no changes in the ISI score (TeII: 1.0, interquartile range [IQR] 6; p = 0.152; BAU: 0.5, IQR 4.5; p = 0.824), HADS-Anxiety score (TeII: -5, IQR 5.3; p = 0.186; BAU: 1.0, IQR 4.0; p = 0.445), or HADS-Depression score (TeII: 0.0, IQR 3.0; p = 0.163; BAU: 0.0, IQR 2.0; p = 0.303) in any of the groups. There was a higher degree of patient satisfaction in the TeII group compared with the BAU group in treatment (median [IQR] score 4 [3-5] vs. 3 [3-4], p < 0.001), headache improvement (median [IQR] 3 [2-4] vs. 2 [1-3], p = 0.002), the headache program (median [IQR] 4 [3-5] vs. 3 [3-4], p < 0.001), and information (median [IQR] 4 [3-5] vs. 3 [3-4], p = 0.005). CONCLUSION: Patients with migraine and/or TTH benefit from a telephone follow-up approach within the first 6 months of their treatment course in terms of more efficient treatment and higher patient satisfaction.

Total tenderness score and pressure pain thresholds in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To investigate whether persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) is associated with more pronounced pericranial tenderness and lower pressure pain thresholds (PPTs) in the head and neck region, compared with healthy controls. METHODS: Patients with persistent post-traumatic headache (n = 100) and age- and gender-matched healthy controls (n = 100) were included between July 2018 and June 2019. Total tenderness score (TTS) was used to assess pericranial tenderness by bilateral manual palpation in eight muscles or tendon insertions. Summation was then used to calculate a TTS from 0 to 48 based on individual right- and left-sided scores; higher TTS score indicated more pronounced pericranial tenderness. PPTs were examined in m. temporalis and m. trapezius (upper and middle part) using an electronic pressure algometer that applies increasing blunt pressure at a constant rate. RESULTS: The TTS score was higher in patients with persistent post-traumatic headache (median, 21; IQR, 12-31), compared with healthy controls (median, 10; IQR, 6-17; P < .001). PPTs were lower in patients with persistent post-traumatic headache than in controls in both the left-sided m. temporalis (mean ± SD, 157.5 ± 59.9 vs. 201.1 ± 65.2; P < .001) and right-sided m. temporalis (mean ± SD, 159.5 ± 63.8 vs. 212.3 ± 61.9; P < .001). Furthermore, patients with persistent post-traumatic headache also had lower left- and right-sided PPTs in the upper as well as middle part of m. trapezius, compared with healthy controls; all P values were .05 or less. CONCLUSIONS: Among patients with persistent post-traumatic headache, pericranial tenderness was more pronounced and PPTs in the head and neck region were lower than in healthy controls free of headache and mild TBI. Further research is needed to better understand the involvement of pericranial myofascial nociceptors in the disease mechanisms underlying post-traumatic headache.

Sensitivity of the SNNOOP10 list in the high-risk secondary headache detection.

AIM: To evaluate the diagnostic accuracy of the SNNOOP10 list in the detection of high-risk headaches. METHODS: Patients that visited the Hospital Clínico San Carlos (Madrid) emergency department due to headache that were allocated to a Manchester Triage System level between critical and urgent were prospectively included but retrospectively analysed. A researcher blind to the patients' diagnosis administered a standardised questionnaire and afterwards a neurologist blind to the questionnaire results diagnosed the patient according to the International Classification of Headache Disorders. The primary endpoint was to assess the sensitivity of the SNNOOP10 list in the detection of high-risk headaches. Secondary endpoints included the evaluation of the sensitivity, specificity, positive predictive value, negative predictive value and area under the curve of each SNNOOP10 item. RESULTS: Between April 2015 and October 2021, 100 patients were included. Patients were 44 years old (inter-quartile range: 33.6-64.7) and 57% were female. We identified 37 different diagnoses. Final diagnosis was a primary headache in 33%, secondary headache in 65% and cranial neuralgia in 2%. There were 46 patients that were considered as having high-risk headache. Patients from the primary headache group were younger and more frequently female. Sensitivity of SNNOOP10 list was 100% (95% confidence interval: 90.2%-100%). The items with higher sensitivity were neurologic deficit or disfunction (75.5%), pattern change or recent onset of the headache (64.4%), onset after 50 years (64.4%). The most specific items were posttraumatic onset of headache (94.5%), neoplasm in history (89.1%) and systemic symptoms (89%). The area under the curve of the SNNOOP10 list was 0.66 (95% CI: 0.55-0.76). CONCLUSION: The red flags from the SNNOOP10 list showed a 100% sensitivity in the detection of high-risk headache disorders.

The role of cytokines in migraine: A systematic review.

BACKGROUND: Cytokines are important endogenous substances that are involved in immune and inflammatory responses. Neurogenic inflammation has been proposed to play a role in migraine involving altered cytokine levels. Therefore, we aimed to provide a systematic review on the current knowledge on cytokine levels in migraine patients during and outside attacks. METHODS: Databases of PubMed and Embase were systematically searched for studies investigating cytokine levels in migraine patients during and outside attacks. RESULTS: Screening yielded identification of 45 articles investigating 18 cytokines in total. We found that the interictal level of the anti-inflammatory cytokine, interleukin 10, was decreased, while the level of transforming growth factor beta 1 was increased in migraine patients compared to controls. Levels of pro-inflammatory cytokines, tumor necrosis factor α and interleukin 6, were increased outside attacks compared to controls. Ictal levels of cytokines were unchanged or varying compared to the interictal state in migraine patients. Three studies reported dynamic cytokines levels during the course of an attack. CONCLUSION: The findings of the current review underline a possible involvement of cytokines in the proposed inflammatory mechanisms of migraine. However, future studies are needed to expand our knowledge of the exact role of cytokines in the migraine pathophysiology with focus on cytokines TNF-α, IL-1ß, IL-6 and IL-10 while applying refined methodology.

Telemedicine in headache care: A systematic review.

OBJECTIVE: Telemedicine is defined as video-based consultations with synchronous video and sound. This systematic review investigated the use of telemedicine for headache patients. The primary outcomes of interest were treatment efficacy, feasibility, safety, convenience, compliance, and patient satisfaction. METHODS: A systematic literature search was performed using PubMed and Embase. Thirteen articles met the eligibility criteria and were included in the review. A systematic review protocol was registered on the International Prospective Register of Systematic Reviews, registration number CRD42021265875. RESULTS: There were no significant differences in treatment efficacy, patient satisfaction, compliance or safety using telemedicine when compared to traditional consultations. Telemedicine was found to be convenient due to being less time-consuming and expensive, especially for patients with limited access to health care. Despite the frequent occurrence of technical errors, telemedicine was found to be feasible. CONCLUSION: Telemedicine consultations are similar in quality to traditional in-office headache consultations and can be a more convenient solution for eligible headache patients.

A history of International Headache Society grants and their impact on headache careers.

BACKGROUND: The International Headache Society has been offering multiple award opportunities for young researchers and clinicians for many years, with the aim of supporting the development of careers in headache science and medicine. METHODS: In order to assess the outcomes of the International Headache Society award grants, a questionnaire was sent to all previous recipients, investigating a series of aspects related to their work, both during and after award completion. RESULTS: Of 44 total questionnaires sent, 36 were returned. Eighty-one percent of the recipients reported to have remained in the headache field since the award, half of them held a current academic position and over three-quarters had stayed in contact with the host institution. The totality of questionnaire responders stated that the grant had had a significantly positive impact on their careers. CONCLUSIONS: The International Headache Society grants have assisted many young researchers in building an academic and clinical career in the field of headache, throughout the years.

Treatment experiences and clinical characteristics in migraine and tension-type headache patients before the first visit to a tertiary headache center.

OBJECTIVES: To investigate previous treatment and clinical characteristics in migraine and tension-type headache patients at their first visit to a tertiary headache center. METHODS: This was a cross-sectional study using data obtained from electronic questionnaires and medical charts. Migraine and tension-type headache patients were investigated at their first visit to the Danish Headache Center. RESULTS: Out of 382 patients the main diagnoses of primary headaches were: 36% with episodic migraine, 43% with chronic migraine, 3% with episodic tension-type headache and 17% with chronic tension-type headache. The majority had attempted non-pharmacological treatment options such as physiotherapy (episodic migraine: 53%, chronic migraine: 68%, episodic tension-type headache: 50%, chronic tension-type headache: 65%) and acupuncture: (episodic migraine: 45%, chronic migraine: 62%, episodic tension-type headache: 17%, chronic tension-type headache: 51%). The majority of migraine patients had tried no more than one triptan (episodic migraine: 71%, chronic migraine: 66%). In total, 35% of episodic migraine and 19% of chronic migraine patients as well as 50% of episodic tension-type headache and 41% of chronic tension-type headache patients had never tried preventive medication. The headache under-response to treatment (HURT) questionnaire score was higher in chronic migraine (score 15) and chronic tension-type headache (score 16) patients than the episodic forms (P < 0.004). CONCLUSIONS: Headache patients had attempted several non-pharmacological treatments prior to their first visit at a tertiary headache center in Denmark. The limited use of acute and preventive treatment before the first visit demonstrates a need for better treatment at the primary and secondary care level.

Low adherence to the guideline for the acute treatment of migraine.

The real-world use of triptans in the treatment of migraine is disappointing. Only 12% of the Danish migraine population purchased a triptan between 2014 and 2019, and only 43% repurchased a triptan after first prescription. The aim of the present study was to assess whether physicians and patients adhere to the therapeutic guideline on acute migraine treatment. We interviewed 299 triptan experienced participants with migraine and 101 triptan naïve participants with migraine from the Danish Migraine Population Cohort, using a semi-structured questionnaire. Descriptive statistical analyses were used to study the association with triptan use and the assessed factors. Among triptan naïve participants with migraine, 64% had consulted their general practitioner about their migraine, of whom only 23% received information about the possibility of triptan treatment. Among triptan experienced participants, 77% had only tried one type of triptan. Only 12% could recall they had been informed by their general practitioner to try each triptan three times before giving up. Twenty percent were informed to try three different triptans in total, if the first did not work. In disagreement with the guideline, participants who reported a low pain reduction by a triptan had only tried one type of triptan. Our study shows a low adherence to therapeutic guideline for the attack treatment of migraine. There is a need for better education of general practitioners regarding treatment of migraine. Future campaigns should aim to inform both the public and the general practitioner about antimigraine treatments.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study.

BACKGROUND: Headache affects 90-99% of the population. Based on the question "Do you think that you never ever in your whole life have had a headache?" 4% of the population say that they have never experienced a headache. The rarity of never having had a headache suggests that distinct biological and environmental factors may be at play. We hypothesized that people who have never experienced a headache had a lower general pain sensitivity than controls. METHODS: We included 99 male participants, 47 headache free participants and 52 controls, in an observer blinded nested case-control study. We investigated cold pain threshold and heat pain threshold using a standardized quantitative sensory testing protocol, pericranial tenderness with total tenderness score and pain tolerance with the cold pressor test. Differences between the two groups were assessed with the unpaired Student's t-test or Mann-Whitney U test as appropriate. RESULTS: There was no difference in age, weight or mean arterial pressure between headache free participants and controls. We found no difference in pain detection threshold, pericranial tenderness or pain tolerance between headache free participants and controls. CONCLUSION: Our study clearly shows that freedom from headache is not caused by a lower general pain sensitivity. The results support the hypothesis that headache is caused by specific mechanisms, which are present in the primary headache disorders, rather than by a decreased general sensitivity to painful stimuli. TRIAL REGISTRATION: Registered at ClinicalTrials.gov ( NCT04217616 ), 3rd January 2020, retrospectively registered.

Nonpharmacological Treatment of Persistent Postconcussion Symptoms in Adults: A Systematic Review and Meta-analysis and Guideline Recommendation.

Importance: Persistent (>4 weeks) postconcussion symptoms (PPCS) are challenging for both patients and clinicians. There is uncertainty about the effect of commonly applied nonpharmacological treatments for the management of PPCS. Objective: To systematically assess and summarize evidence for outcomes related to 7 nonpharmacological interventions for PPCS in adults (aged >18 years) and provide recommendations for clinical practice. Data Sources: Systematic literature searches were performed via Embase, MEDLINE, PsycINFO, CINAHL, PEDro, OTseeker, and Cochrane Reviews (via MEDLINE and Embase) from earliest possible publication year to March 3, 2020. The literature was searched for prior systematic reviews and primary studies. To be included, studies had to be intervention studies with a control group and focus on PPCS. Study Selection: A multidisciplinary guideline panel selected interventions based on frequency of use and need for decision support among clinicians, including early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of neck and back, oculomotor vision treatment, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. To be included, studies had to be intervention studies within the areas of the predefined clinical questions, include a control group, and focus on symptoms after concussion or mild traumatic brain injury. Data Extraction and Synthesis: Extraction was performed independently by multiple observers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data abstraction and data quality assessment. Included studies were assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Cochrane Risk of Bias (randomized clinical trials) tool. Meta-analysis was performed for all interventions where possible. Random-effects models were used to calculate pooled estimates of effects. The level and certainty of evidence was rated and recommendations formulated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Main Outcomes and Measures: All outcomes were planned before data collection began according to a specified protocol. The primary outcomes were the collective burden of PPCS and another outcome reflecting the focus of a particular intervention (eg, physical functioning after graded exercise intervention). Results: Eleven systematic reviews were identified but did not contribute any primary studies; 19 randomized clinical trials comprising 2007 participants (1064 women [53.0%]) were separately identified and included. Evidence for the 7 interventions ranged from no evidence meeting the inclusion criteria to very low and low levels of evidence. Recommendations were weak for early information and advice, graded physical exercise, vestibular rehabilitation, manual treatment of the neck and back, psychological treatment, and interdisciplinary coordinated rehabilitative treatment. No relevant evidence was identified for oculomotor vision treatment, so the panel provided a good clinical practice recommendation based on consensus. Conclusions and Relevance: Based on very low to low certainty of evidence or based on consensus, the guideline panel found weak scientific support for commonly applied nonpharmacological interventions to treat PPCS. Results align with recommendations in international guidelines. Intensified research into all types of intervention for PPCS is needed.

Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis.

BACKGROUND: Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients. FINDINGS: We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients' age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0-9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7-20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18-1.47, p = 0.213). CONCLUSION: Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.

Psychiatric and cognitive comorbidities of persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To investigate the association of psychiatric and cognitive comorbidities with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). METHODS: A total of 100 patients with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls free of mild TBI were enrolled between July 2018 and June 2019. Quality of sleep was evaluated using the Pittsburgh Sleep Quality Index, while symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Cognitive impairment was evaluated using the Montreal Cognitive Assessment questionnaire, while post-traumatic stress disorder (PTSD) was assessed using the Harvard Trauma Questionnaire. RESULTS: In 100 patients with persistent PTH, 85% reported poor quality sleep, compared with 42% of healthy controls (P < 0.01). The relative frequency of probable to high risk of anxiety was 52% in the persistent PTH group vs. 8% in healthy controls (P < 0.01), while the relative frequency of probable to high risk of depression was 42% in the persistent PTH group vs. 2% in healthy controls (P < 0.01). Furthermore, 27% of the patients with persistent PTH had mild cognitive impairment while 10% had probable PTSD. CONCLUSIONS: Poor quality of sleep as well as symptoms suggestive of anxiety and depression were more common in patients with persistent PTH than healthy controls. Clinicians should screen patients with persistent PTH for these comorbidities and develop treatment plans that account for their presence.